The transforming growth factor b1 (TGFbl) signaling pathway is clinically very important. It is directly implicated in several birth defects, including Marfan Syndrome, Hereditary Hemorrhagic Telangiectasia (HHT), Camurati-Engelmann disease and cleft palate, as well as being involved in the etiology of the two most important multifactorial diseases affecting humans, namely cancer and cardiovascular (CV) disease. TGFbl is also a key regulator of immunomodulation. Genes encoding components of the TGFbl signaling pathway including TGFB1 have been shown to be functionally polymorphic in humans, and genetic associations have been found between carriers of specific TGFB1 polymorphic variants and disease susceptibility for cancer, atherosclerosis, myocardial infarction (Ml), hypertension and other cardiovascular diseases. The goal of this research is to identify and characterize the differential functions of genetic variants that influence the activity of TGFbl action in vivo, particularly with respect to angiogenesis and CV disease. The specific objective of this proposal is to characterize variants responsible for genetic modification within the TgfbmS locus on mouse chromosome 12 and to determine their role in vascular biology, and the role of orthologous genes at 2p25.1 in risk for Ml in humans. This information:a)Will increase our understanding of molecular pathways involved in TGFbl-mediated vascular remodeling, b) May provide screening tools for assessment of disease risk in ailments known to have a TGFB1 associationc) Will provide targets for prophylactic drug development of such diseases d) May provide predictive markers for response to anti-TGFb drug therapies